Osteoporosis, which has been defined as a “state of low bone mass”, is one of the major problems in our aging society. It is a disease characterized by micro architectural deterioration of bone tissue leading to enhanced bone fragility and consequent increase in fracture risk in older members of the population. It is known to affect >50% of women and 30% men over the age of 50 years. In women, there is also an accelerated rate of bone loss immediately and for variable number of years following menopause.
Efforts to reduce this risk factor and incidence of fractures have resulted in the development of compounds that conserve skeletal mass by inhibiting bone resorption and/or by enhancing bone formation (Dwivedy I, Ray S, 1995 “Recent developments in the chemotherapy of osteoporosis” Progress in Drug Research 45, 289-338, Editor E Jucker, Birkhauser Vela; Marshall D H, Horsmann A, Nordin B E C, 1977, “The prevention and management of post-menopausal osteoporosis” Acta Obstet Gynecol Scand (Suppl) 65:49-56; Hutchinson T A, Polansky S M, Feinstein A R, 1979, “Postmenopausal estrogen protect against fractures of hip and distal radius: A care-control study” Lancet 2:705-709. Estrogen replacement therapy also has positive effect on CVS & CNS related disorders (Lobo R A, 1990, “Cardiovascular implication of estrogen replacement therapy” Obstetrics & Gynaecology 75:185-245; Mendelson M E, Karas R H, 1994, “Estrogen and the blood vessel wall” Current opinion in Cardiology 1994:619-626; Stampfer M J, Colditz G A, 1991, “Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiological evidence” Preventive Medicine 20:47-63).
Most of the pharmacological agents available for clinical use such as calcium, vitamin D and its analog, estrogen, calcitonin, bisphosphonates, raloxifene etc. act by decreasing the rate of bone resorption, thereby slowing the rate of bone loss. Timely administration of such antiresorptive agents prevents bone loss. However, bone once lost cannot be recovered by use of such antiresorptive agents.
In traditional medicine, there are many natural crude drugs that have the potential to treat bone diseases. However, not much laboratory work has been reported evaluating their possible development and use, except ipriflavone, an isoflavonoid, which has been used clinically for this indication.
The compounds included in this patent have been demonstrated to promote proliferation and differentiation of osteoblasts, matrix maturation and mineralization in vitro in a number of assays and increase bone mineral density and bone mechanical strength following prolonged treatment in vivo and would be of tremendous use not only in fast fracture healing and management of age-related (Type-II) osteoporosis, but might also help in attaining higher peak bone mass when administered during the period of growth and development, promote new bone formation in vitro/in vivo for replacement of defective bone and prevention of resorption in estrogen deficiency states including post-menopausal osteoporosis. Some of the compounds of the present invention show good systemic availability in experimental animals correlating well with its pharmacodynamic properties.
Currently the only agents reported to show bone formation activity include (a) parathyroid hormone, which is to be administered parenterally and increases bone resorption at higher doses, (b) fluoride, excessive intake of which is also known to cause osteoporosis and (c) androgens by virtue of their anabolic activity. This is the first agent of its kind from natural sources and would be developed as an oral formulation for human use and welfare.
The benzfurochromenes constitute the second largest group of natural isoflavonoids, which contain a tetracyclic ring system derived from the isoflavonoid skeleton by an ether linkage between the 4- and 2′-positions [(a) Dewich, P. M. In Harborne, J. B., Ed.; The Flavanoids: Advances in Research Since 1986; Chapman and Hall: London, 1994; (b) Tanaka, H.; Oh-Uchi, T.; Etoh, H.; Shimizu, H.; Tateishi, Y. Phytochemistry 2002, 60, 789]. Various biological activities are associated with this compound, which include potent phytoalexins (Mansfield, J. W. In Phytoalexins; Bailey, J. A., Mansfield, J. W., Eds.; Glasgow, 1982.), antitoxin and antiviral (Nakagawa, M.; Nakanishi, K.; Darko, L. L.; Vick, J. A. Tetrahedron Lett. 1982, 23, 3855.), antifungal ((a) Maximo, P.; Lourenc, o, A. Phytochemistry 1998, 48, 359; (b) Perrin, D. R. Tetrahedron Lett. 1964, 1, 29.), and antibacterial (Ingham, J. L. In Progress in the Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer: New York, 1983; Vol. 43, pp 1-266.) properties. We are involved in the synthesis of natural products such as flavonoids, terpenes and other related biologically important oxygen heterocycles and evaluate their biological properties in various in-house screening models. Recently we prepared a series of benzfurochromenes and related compounds for the prevention or treatment of various medical indications associated with estrogen independent or dependent diseases or syndromes preferably in prevention or treatment of diseases and syndromes caused in humans and animals, in particular: Osteoporosis, bone loss, bone formation; bone formation during Type-II/age related/senile osteoporosis, period of development and growth to attain higher peak bone mass, bone fracture healing, promotion of new bone formation in vitro/in vivo for replacement of defective bone.
Some of the novel synthesized benzfurochromenes particularly 3-allyloxy-4-methyl-6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromene (S-007-1500) showed stimulation in ALP activity in calvarial derived osteoblasts from 10−12M to 10−6M concentrations in repeated screening. Such encouraging results prompted us to prepare several nature-mimicking benzfurochromenes and their related compounds for the prevention or treatment of various medical indications associated with estrogen independent or dependent diseases or syndromes preferably in prevention or treatment of diseases and syndromes caused in humans and animals. The detailed biological studies (in vitro and in vivo) on the synthesized compounds are mentioned in biological evaluation section of the draft.
Osteoporosis is one of the major problems in our aging society. Osteoporosis results in bone fracture in older members of the population, especially in post-menopausal women. In traditional medicine, there are many natural crude drugs that have the potential for use to treat bone diseases. So far, there is no drug available which show osteogenic and anti-osteoclastogenic activity. Therefore, there is an urgent need to discover and develop a drug, which possess the ideal pharmacological profile and promote new bone formation.